Is MSH2 p.Ser585Phe (c.1754C>T) pathogenic?

MSH2 p.Ser585Phe (c.1754C>T) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.9594); Very rare (popmax 0.00167%, amr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ser585Phe (c.1754C>T)?

MSH2 p.Ser585Phe (c.1754C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Muir-Torre syndrome, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser585Phe (c.1754C>T) in the general population?

MSH2 p.Ser585Phe (c.1754C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MSH2 p.Ser585Phe (c.1754C>T)?

AlphaMissense predicts likely pathogenic (score 0.9594) — an in-silico prediction, not a clinical call.

MSH2 p.Ser585Phe

c.1754C>T · rs1280971849 · VCV576789

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.9594	likely pathogenic
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -12.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,814 alleles

Overall 6.71e-05% 1/1,490,570 alleles · very rare exomes 1/1,338,270 · genomes 0/152,300 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MSH2
Protein: p.Ser585Phe
Coding: c.1754C>T
MANE Select: NM_000251
dbSNP: rs1280971849
Type: single nucleotide variant
Location: chr2:47471057 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 585: an α-helix

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Muir-Torre syndrome hereditary neoplastic syndrome

Similar variants

MSH2 p.Ser585= Benign/Likely benign ★★ same residue
MSH2 p.Ser585Ala Likely benign ★ same residue
MSH2 p.Ser585fs Pathogenic ★★ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-2A>C Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/msh2-p-ser585phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown